Aziridine containing dna alkylating agents

ABSTRACT

Provided herein are compounds of formula (I)-(VI), wherein the variables are defined herein, processes of making them, and methods of treating cancer comprising administering such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 62/184,129, filed Jun. 24, 2015, the contentof which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION

The present invention provides compounds suitable as therapeutic agents,pharmaceutical compositions of such compounds and methods of treatingcancer in cancer patients, and so relates to the fields of biology,chemistry, and medicine.

BACKGROUND OF THE INVENTION

Cancer is one of the major causes of human morbidity and mortality.Cancer treatment is challenging because it is difficult to kill cancercells without damaging or killing normal cells. Damaging or killingnormal cells during cancer treatment is a cause of adverse side effectsin patients and can limit the amount of anti-cancer drug administered toa cancer patient. There remains a need for compounds suitable fortreating cancer patients.

SUMMARY

In one aspect, In one aspect, provided herein are compounds selectedfrom:

wherein the variables are defined and illustrated herein below. Asprovided herein the compounds include mixtures of stereoisomers, such asenantiomers, and separated individual enantiomers and racemic andnonracemic mixtures thereof. Without being bound by theory, in certainembodiments, the compounds provided here act as prodrugs that can beactivated in or around the hypoxic conditions existing in or aroundtumors.

In another aspect, provided herein are methods of preparing thecompounds provided herein.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein and at least one pharmaceuticallyacceptable excipient.

In another aspect, provided herein are methods of treating cancercomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound provided herein, or a therapeuticallyeffective amount of a composition provided herein.

BRIEF DESCRIPTION OF FIGURES

The comparative tumor volume reductions for certain compounds aregraphically illustrated in FIGS. 1A-1C.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are provided to assist the reader. Unlessotherwise defined, all terms of art, notations, and other scientific ormedical terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the chemical andmedical arts. In some cases, terms with commonly understood meanings aredefined herein for clarity and/or for ready reference, and the inclusionof such definitions herein should not be construed as representing asubstantial difference over the definition of the term as generallyunderstood in the art.

All numerical designations, e.g., pH, temperature, time, concentration,and weight, including ranges of each thereof, are approximations thattypically may be varied (+) or (−) by increments of 0.1, 1.0, or 10.0,as appropriate. All numerical designations may be understood as precededby the term “about”. Reagents described herein are exemplary andequivalents of such may be known in the art.

“A,” “an,” and, “the” include plural referents unless the contextclearly dictates otherwise. Thus, for example, reference to a compoundrefers to one or more compounds or at least one compound. As such, theterms “a” (or “an”), “one or more”, and “at least one” are usedinterchangeably herein.

As used herein, the term “comprising” is intended to mean that thecompositions and methods include the recited elements, but not excludingothers. “Consisting essentially of” when used to define compositions andmethods, shall mean excluding other elements of any essentialsignificance to the composition or method. “Consisting of” shall meanexcluding more than trace elements of other ingredients for claimedcompositions and substantial method steps. Embodiments defined by eachof these transition terms are within the scope of this invention.Accordingly, it is intended that the methods and compositions caninclude additional steps and components (comprising) or alternativelyincluding steps and compositions of no significance (consistingessentially of) or alternatively, intending only the stated method stepsor compositions (consisting of).

“C_(x)-C_(y)” or “C_(x-y)” before a group refers to a range of thenumber of carbon atoms that are present in that group. For example,C₁-C₆ alkyl refers to an alkyl group having at least 1 and up to 6carbon atoms.

“Alkoxy” refers to −0-Alkyl.

“Amino” refers to NR^(p)R^(q) wherein R^(p) and R^(q) independently arehydrogen or C₁-C₆ alklyl, or R^(p) and R^(q) together with the nitrogenatom they are bonded to form a 4-15 membered heterocycle.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6carbon atoms. “C_(x-y) alkyl” refers to alkyl groups having from x to ycarbon atoms. This term includes, by way of example, linear and branchedhydrocarbyl groups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl(CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl((CH₃)₂CHCH₂—), sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—),n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Alkenyl” refers to a linear or branched hydrocarbyl group having from 2to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2to 4 carbon atoms and having at least 1 site of vinyl unsaturation(>C═C<). For example, C_(x-y) alkenyl refers to alkenyl groups havingfrom x to y carbon atoms and is meant to include, for example, ethenyl,propenyl, 1,3-butadienyl, and the like.

“Alkynyl” refers to a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical 2 to 10 carbon atoms and in someembodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms andcontaining at least one triple bond. The term “alkynyl” is also meant toinclude those hydrocarbyl groups having one triple bond and one doublebond. For example, C₂₋₆ alkynyl includes ethynyl, propynyl, and thelike.

“Aryl” refers to an aromatic group of from 6 to 14 carbon atoms and noring heteroatoms and having a single ring (e.g., phenyl) or multiplecondensed (fused) rings (e.g., naphthyl or anthryl). For multiple ringsystems, including fused, bridged, and spiro ring systems havingaromatic and non-aromatic rings that have no ring heteroatoms, the term“Aryl” or “Ar” applies when the point of attachment is at an aromaticcarbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl groupas its point of attachment is at the 2-position of the aromatic phenylring).

“Cycloalkyl” refers to a saturated or partially saturated cyclic groupof from 3 to 14 carbon atoms and no ring heteroatoms and having a singlering or multiple rings including fused, bridged, and spiro ring systems.For multiple ring systems having aromatic and non-aromatic rings thathave no ring heteroatoms, the term “cycloalkyl” applies when the pointof attachment is at a non-aromatic carbon atom (e.g.,5,6,7,8,-tetrahydronaphthalene-5-yl). The term “cycloalkyl” includescycloalkenyl groups. Examples of cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl,and cyclohexenyl.

“Ether” refers to a C₁-C₆ alkyl group substituted with 1-3 C₁-C₆ alkoxygroups, wherein alkoxy refers to —O-alkyl.

“Halo” refers to one or more of fluoro, chloro, bromo, and iodo.

“Heteroaryl” refers to an aromatic group of from 1 to 14 carbon atomsand 1 to 6 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur and includes single ring (e.g. imidazolyl-2-yl andimidazol5-yl) and multiple ring systems (e.g. imidazopyridyl,benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl). For multiplering systems, including fused, bridged, and spiro ring systems havingaromatic and non-aromatic rings, the term “heteroaryl” applies if thereis at least one ring heteroatom, and the point of attachment is at anatom of an aromatic ring (e.g., 1,2,3,4-tetrahydroquinolin-6-yl and5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogenand/or the sulfur ring atom(s) of the heteroaryl group are optionallyoxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonylmoieties. The term heteroaryl includes, but is not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzothienyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isoquinolyl,isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, oxazolidinyl, oxazolyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazolyl, pyridoimidazolyl, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, thiadiazinyl, thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl and xanthenyl.

“Heterocyclic” or “heterocycle” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated or partially saturated cyclic group having from 1to 14 carbon atoms and from 1 to 6 heteroatoms selected from the groupconsisting of nitrogen, sulfur, or oxygen and includes single ring andmultiple ring systems including fused, bridged, and spiro ring systems.For multiple ring systems having aromatic and/or non-aromatic rings, theterms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or“heterocyclyl” apply when there is at least one ring heteroatom, and thepoint of attachment is at an atom of a non-aromatic ring (e.g.,1,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, anddecahydroquinolin-6-yl). In some embodiment, the heterocyclic groupsherein are 3-15 membered, 4-14 membered, 5-13 membered, 7-12, or 5-7membered heterocycles. In some other embodiment, the heterocyclescontain 4 heteroatoms. In some other embodiment, the heterocyclescontain 3 heteroatoms. In another embodiment, the heterocycles containup to 2 heteroatoms. In some embodiments, the nitrogen and/or sulfuratom(s) of the heterocyclic group are optionally oxidized to provide forthe N-oxide, sulfinyl, sulfonyl moieties. Heterocyclyl includes, but isnot limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl,piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl,morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbonatoms (e.g., C₃₋₁₀) refers to the total number of carbon atoms in theportion of the heterocyclyl group exclusive of the number ofheteroatoms. A divalent heterocyclic radical will have the appropriatelyadjusted hydrogen content.

The term “optionally substituted” refers to a substituted orunsubstituted group. The group may be substituted with one or moresubstituents, such as e.g., 1, 2, 3, 4 or 5 substituents. Preferably,the substituents are selected from the group consisting of oxo, halo,—CN, NO₂, —N₂ ⁺, —CO₂R¹⁰⁰, —OR¹⁰⁰, —SR¹⁰⁰, —SOR¹⁰⁰, —SO₂R¹⁰⁰,—NR¹⁰⁰SO₂R¹⁰⁰, —NR¹¹R¹⁰², CONR¹⁰¹R¹⁰², —SO₂NR¹⁰¹R¹⁰², C₁-C₆ alkyl, C₁-C₆alkoxy, —CR¹⁰⁰═C(R¹⁰⁰)₂, —CCR¹⁰⁰, C₃-C₁₀ cycloalkyl, C₃-C₁₀heterocyclyl, C₆-C₁₂ aryl and C₂-C₁₂ heteroaryl, or a divalentsubstituent such as —O—(CH₂)—O—, —O—(CH₂)₂—O—, and, 1-4 methylsubstituted version thereof, wherein each R¹⁰⁰, R¹⁰¹, and R¹⁰²independently is hydrogen or C₁-C₈ alkyl; C₃-C₁₂ cycloalkyl; C₃-C₁₀heterocyclyl; C₆-C₁₂ aryl; or C₂-C₁₂ heteroaryl; or R¹⁰¹ and R¹⁰²together with the nitrogen atom they are attached to form a 5-7 memberedheterocycle; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with 1-3 halo, 1-3 C₁-C₆ alkyl, 1-3C₁-C₆ haloalkyl or 1-3 C₁-C₆ alkoxy groups. Preferably, the substituentsare selected from the group consisting of chloro, fluoro includingtrifluoro, —OCH₃, methyl, ethyl, iso-propyl, cyclopropyl, OH, OAc, 5-6membered heterocyclyl containing 1-3 heteroatoms such as nitrogen andoxygen optionally substituted with 1-3 C₁-C₆ alkyl or C₆-C₁₀ arylgroups, 5-6 membered heteroaryl containing 1-3 heteroatoms such asnitrogen and oxygen optionally substituted with 1-3 C₁-C₆ alkyl groups,—CO₂H and salts and C₁-C₆ alkyl esters thereof, CONMe₂, CONHMe, CONH₂,—SO₂Me, —SO₂NH₂, —SO₂NMe₂, —SO₂NHMe, —NHSO₂Me, —NHSO₂CF₃, —NHSO₂CH₂C₁,—NO₂, —NH₂, —NMe₂, —OCF₃, —CF₃ and —OCHF₂. Other optional substituentsinclude those illustrated in the table herein below.

“Prodrug” refers to a compound that, after administration, ismetabolized or otherwise converted to a biologically active or moreactive compound (or drug) with respect to at least one property. Aprodrug, relative to the drug, is modified chemically in a manner thatrenders it, relative to the drug, less active or inactive, but thechemical modification is such that the corresponding drug is generatedby metabolic or other biological processes after the prodrug isadministered. A prodrug may have, relative to the active drug, alteredmetabolic stability or transport characteristics, fewer side effects orlower toxicity, or improved flavor (for example, see the referenceNogrady, 1985, Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, pages 388-392, incorporated herein byreference). A prodrug may be synthesized using reactants other than thecorresponding drug.

“Administering” or “administration of” a drug to a patient (andgrammatical equivalents of this phrase) refers to direct administration,which may be administration to a patient by a medical professional ormay be self-administration, and/or indirect administration, which may bethe act of prescribing a drug. For example, a physician who instructs apatient to self-administer a drug and/or provides a patient with aprescription for a drug is administering the drug to the patient.

“Cancer” refers to leukemias, lymphomas, carcinomas, and other malignanttumors, including solid tumors, of potentially unlimited growth that canexpand locally by invasion and systemically by metastasis. Examples ofcancers include, but are not limited to, cancer of the adrenal gland,bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head andneck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate,parathyroid, skin, stomach, and thyroid. Certain other examples ofcancers include, acute and chronic lymphocytic and granulocytic tumors,adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and insitu carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant celltumor, glioblastoma multiforma, hairy-cell tumor, intestinalganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma,Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid,malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor,medullary carcinoma, metastatic skin carcinoma, mucosal neuroma,myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic andother sarcoma, ovarian tumor, pheochromocytoma, polycythermia vera,primary brain tumor, small-cell lung tumor, squamous cell carcinoma ofboth ulcerating and papillary type, hyperplasia, seminoma, soft tissuesarcoma, retinoblastoma, rhabdomyosarcoma, renal cell tumor, topicalskin lesion, veticulum cell sarcoma, and Wilm's tumor.

“Patient” and “subject” are used interchangeably to refer to a mammal inneed of treatment for cancer. Generally, the patient is a human.Generally, the patient is a human diagnosed with cancer. In certainembodiments a “patient” or “subject” may refer to a non-human mammalused in screening, characterizing, and evaluating drugs and therapies,such as, a non-human primate, a dog, cat, rabbit, pig, mouse or a rat.

“Solid tumor” refers to solid tumors including, but not limited to,metastatic tumors in bone, brain, liver, lungs, lymph node, pancreas,prostate, skin and soft tissue (sarcoma).

“Therapeutically effective amount” of a drug refers to an amount of adrug that, when administered to a patient with cancer, will have theintended therapeutic effect, e.g., alleviation, amelioration, palliationor elimination of one or more manifestations of cancer in the patient. Atherapeutic effect does not necessarily occur by administration of onedose, and may occur only after administration of a series of doses.Thus, a therapeutically effective amount may be administered in one ormore administrations.

“Treating,” “treatment of,” or “therapy of” a condition or patientrefers to taking steps to obtain beneficial or desired results,including clinical results. For purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationor amelioration of one or more symptoms of cancer; diminishment ofextent of disease; delay or slowing of disease progression;amelioration, palliation, or stabilization of the disease state; orother beneficial results. Treatment of cancer may, in some cases, resultin partial response or stable disease.

Compounds

In one aspect, provided herein is a compound selected from:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of each thereof, wherein

R¹ is: hydrogen, —N₃, CN, halo, NR²¹R²², —OR²³, —SO₂(C₁-C₆ alkyl), C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15membered heterocycle, 5-15 membered heteroaryl, or ether;

each R²¹ and R²² independently is hydrogen, hydroxy, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 memberedheterocycle, 5-15 membered heteroaryl, or —SO₂(C₁-C₆ alkyl); or R²¹ andR²² together with the nitrogen atom they are bonded to form a 4-15membered heterocycle or a 5-15 membered heteroaryl;

R²³ is hydrogen, C₁-C₆ alkyl, or C₆-C₁₀ aryl;

R² and R³ are independently hydrogen or halo;

R⁴ is hydrogen, halo, C₁-C₆ alkoxy, C₁-C₆ alkyl, or C₆-C₁₀ aryl,

R⁵, R⁷, R⁹, R¹², and R¹⁵ independently are hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 memberedheterocycle, 5-15 membered heteroaryl; or R⁴ and R⁵ together with theintervening carbon atoms between them form a C₅-C₆ cycloalkyl ring;

R⁶ and R¹⁰ independently are hydrogen or halo;

R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or 5-15membered heteroaryl;

each R¹¹ independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, or C₆-C₁₀ aryl;

R¹³, R¹⁴, R¹⁶, and R¹⁷ are independently hydrogen, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkyny, or C₁-C₆ alkoxy;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle,heteroaryl, alkoxy and ether groups are optionally substituted.

In one embodiment, the compound provided is of formula:

In another embodiment, R¹ is a non-hydrogen substituent. In anotherembodiment, R² and R³ are hydrogen. In another embodiment, R⁴ ishydrogen or halo. In another embodiment, R⁴ is hydrogen. In anotherembodiment, R⁴ is halo. In another embodiment, R⁴ is fluoro. In anotherembodiment, R⁴ and R⁵ together form a 5 membered cycloalkyl group. Inanother embodiment, R¹ is a non-hydrogen substituent, R² and R³ arehydrogen, and R⁴ is hydrogen or halo, or R⁴ and R⁵ together form a 5membered cycloalkyl group. In another embodiment, R⁵ is a non-hydrogensubstituent. In another embodiment, R¹ is NR²¹R²².

In another embodiment, the compound provided is of formula:

In another embodiment, R⁸ is hydrogen. In another embodiment, R⁸ isC₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl. In another embodiment, R⁹is optionally substituted C₁-C₆ alkyl.

In another embodiment, the compound provided is of formula:

In another embodiment, R⁷ is optionally substituted C₁-C₆ alkyl.

In another embodiment, the compound provided is of formula:

In another embodiment, R¹² is optionally substituted C₁-C₆ alkyl.

In another embodiment, the compound provided is of formula:

In another embodiment, R¹⁵ is optionally substituted C₁-C₆ alkyl.

In another embodiment, the compound provided is of formula:

In another embodiment, R⁷ is optionally substituted C₁-C₆ alkyl.

Certain non-limiting and illustrative compounds provided and/or utilizedherein are tabulated below along with their anti-cancer abilities undernitrogen and under air.

compound structure IC₅₀ (N₂) μM IC₅₀ (air) μM 2118

0.01 6.2 2119

0.03 0.8 2127

0.02 0.9 2128

0.02 18 2129

0.08 0.7 2130

0.005 1.3 2136

0.1 24 2137

0.02 2.2 2138

0.006 0.3 2139

0.004 0.3 2141

0.08 0.5 2145

0.4 170 2147

1.1 310 2149

0.03 7.5 2151

0.01 6 2334

0.009 0.14 2387

3.8 23 2501

0.05 21 2518

0.6 420 2519

>500 >500 2520

8.8 20 2523

0.02 0.4 2525

0.02 0.7 2527

0.09 39 2529

0.2 33 2535

26 500 2537

0.3 53 2542

1.5 3.4 2544

0.2 45 2547

2.6 320 2550

1.8 29 2551

0.1 20 2552

0.1 23 2554

0.1 3 2556

0.7 17 2560

3.7 40 2561

0.2 29 2563

3.2 15 2565

0.1 18 2566

0.1 23 2567

0.3 270 2568

0.3 350 2569

0.05 2 2572

1.6 29 2574

0.1 29 2576

0.1 1.8 2578

6 28 2579

1.3 2.6 2580

3.7 20 2582

0.1 18 2588

1.3 10 2589

0.1 9.6 2590

2.9 15 2591

0.1 19 2592

0.7 3.3 2594

0.15 7.4 2595

0.2 3.2 2599

0.08 1.5 2600

0.05 2.8 2602

0.02 0.25 2603

0.3 29 2604

0.7 320 2608

0.3 3.1 2609

0.4 370 2610

51 350 2611

0.2 14 2613

0.3 26 2615

320 350 2616

3.7 17 2619

2.3 99 2620

2.5 7.4 2621

0.3 39 2624

0.5 160 2626

0.6 3.3 2627

0.5 32 2633

0.3 83 2635

0.22 13 2637

0.8 23 2640

1.1 83 2643

0.6 37 2645

1.6 30 2652

0.02 2.2 2654

260 >500 2656

0.1 2.4 2658

0.3 86 2662

0.03 22 2664

0.4 0.6 2666

2 24 2672

3.1 180 2675

0.05 3.4 2676

0.1 3.7 2678

0.4 32 2679

2.9 34 2680

2.6 110 2681

0.3 28 2686

3.1 79 2687

2.2 15 2689

0.6 43 2690

3.2 99 2691

2.3 2.3 2692

2.7 6.2 2693

0.4 1.9 2695

4.2 130 2696

7.4 310 2697

0.5 1.5 2698

1.6 3.7 2700

350 370 2701

1.3 66 2702

0.8 47 2703

0.2 99 2706

0.03 14 2707

0.1 0.2 2708

3 20 2709

2.4 26 2710

0.03 3 2712

0.2 0.3 2714

0.5 94 2721

0.02 9 2722

0.9 5 2723

29 420 2726

0.2 19 2727

0.2 31 2728

0.2 22 2730

0.7 22 2731

0.1 13 2732

0.2 23 2733

0.03 2.8 2734

1.6 2.5 2735

2 3.1 2736

2.8 150 2737

0.2 21 2738

0.2 20 2740

1.4 24 2742

0.1 3 2743

0.2 3.7 2744

0.05 2.7 2745

0.3 58 2746

2.6 220 2747

0.3 39 2748

0.3 38 2749

0.1 3 2750

2.4 23 2751

1.7 36 2752

5.7 270 2753

3.2 19 2755

0.03 4.4 2756

2.8 45 2757

3.8 380 2759

0.4 100 2760

2.4 53 2763

0.1 5 2765

0.03 8.1 2766

0.7 4.8 2767

0.2 2.3 2771

0.03 14 2772

0.05 26 2773

0.7 16 2774

0.8 3.5 2775

0.3 2.5 2776

0.4 2.5 2777

0.01 3.4 2782

1.7 41 2783

1.7 51 2785

1.6 47 2786

2.5 69 2787

0.02 2.3 2788

1.3 22 2789

2.4 36 2790

1.8 4 2792

0.2 3.7 2793

0.4 4 2798

0.6 32 2799

2.3 37 2800

1.3 30 2801

2.2 47 2802

2.8 22 2803

0.3 150 2804

0.6 310 2805

1.8 320 2806

0.3 5.4 2807

0.03 13 2811

0.1 8.4 2821

0.05 5 2822

0.3 3.1 2824

0.02 1.7

EXAMPLES Example 1. Synthesis of TH 2565 and 2566

Compound B

NaBH₄ (0.38 g) was added to a solution of compound A (1.65 g) in 15 mLof methanol at room temperature. The solution was stirred at for 30 min.The solution was diluted with water (50 mL) and extracted with DCM. Theorganic layer was dried with Na₂SO₄. The solvent was removed to getcompound B (1.6 g).

Compound D

Under argon, to a suspension of compounds B (1.36 g), compound C (3.7g), and PPh₃ (3.2 g) in THF (40 mL) was added DIAD (2.5 mL) at 0° C. Themixture was stirred from 0° C. to room temperature for 2 hrs. Afterremoval of solvent under vacuum, the residue was separated by flashchromatography on silica gel (Hex:AcOEt=100:70 (v/v)) to yield 1.3 g ofcompound D.

TH 2937

A mixture of compound D (1.3 g), Ag₂O (2.5 g), DIEA (2 mL) in THL (30mL) was stirred at 50° C. for 5 hrs. After removal of solvent undervacuum, the residue was separated by flash chromatography on silica gel(AcOEt: 20% MeOH/DCM=70:30 (v/v)) to yield light liquid 0.7 g of TH2937.

TH 2565 and TH 2566

1.0 g of TH 2937 was separated by chiral column to get 0.48 g of TH 2565and 0.47 g of TH 2566. 1HNMR (CDCl₃) for TH2565 and TH2566. 1.65 (d,J=6.4 Hz, 3H), 2.02-2.22 (m, 8H), 5.70-5.75 (m, 1H), 7.57 (d, J=8.4 Hz,2H), 8.23 (d, J=8.4 Hz, 2H).

1. Synthesis of Compound 2

-   -   To a solution of compound 1 (2.9 g, 22.83 mmol) in THF (35 mL)        was added LiHMDS (1.0 M THF solution, 24 mL, 24 mmol) at −40 C        under argon. The mixture was stirred at −40 C for 15 minutes.    -   The aldehyde was added slowly with inner temperature kept below        −30 C.    -   The mixture was stirred at −40 C for 75 minutes before quenched        with aqueous saturated NH4Cl solution (10 mL).    -   The reaction mixture was extracted with EtOAc (40 mL×3), washed        with brine (50 mL), dried over Na₂SO₄.    -   The solvents were removed under reduced pressure and the residue        was purified via flash column to afford clear oil (1.5 g, yield        33%).

1HNMR (CDCl₃, 400 MHz) δ: 7.97 (s, 1H), 4.22 (m, 1H), 4.00 (s, 3H),2.24-2.14 (m, 1H), 1.06 (d, J=6.4 Hz, 3H), 0.93 (dd, J=1.2, 6.4 Hz, 3H)

2. Synthesis of Compound 3

-   -   To a mixture of compound 2 (1.5 g, 7.54 mmol) in THF (60 mL) was        added LiHMDS (1.0 M THF solution, 8.3 mL, 8.3 mmol) at −78 C        under argon.    -   The mixture was stirred at −78 C for 10 minutes and then a        solution of bromine compound (3.7 g, 11.31 mmol) was added        slowly.    -   The mixture was stirred at −78 C and then room temperature        overnight.    -   Solvents were removed under reduced pressure and the residue was        purified via flash column to afford a light yellow oil (1.8 g,        49% yield)

1HNMR (CDCl₃, 400 MHz) δ: 8.01 (s, 1H), 5.18 (t, J=6.4 Hz, 1H), 4.07 (s,3H), 3.59-3.02 (m, 8H), 2.41-2.36 (m, 1H), 1.83 (d, J=6.8 Hz, 3H), 0.92(d, J=6.8 Hz, 3H).

3. Synthesis of TH 2567/2568

-   -   A mixture of compound 3 (1.8 g, 3.67 mmol), DIPEA (3 mL), Ag₂O        (10 g) in THF (45 mL) was stirred at 65 C under argon for 4        hours. Solid was filtered and the filtrate was concentrated to        dryness, purified via flash column to afford a clear oil (1.02        g, 81% yield).

1HNMR (CDCl₃, 400 MHz) δ: 8.04 (s, 1H), 5.16 (t, J=6.8 Hz, 1H), 4.10 (s,3H), 2.50-2.41 (m, 1H), 2.24-2.01 (m, 8H), 1.19 (d, J=6.4 Hz, 3H), 0.81(d, J 6.4 Hz, 3H).

-   -   This mixture was separated via chiral HPLC to afford TH 2567 and        TH 2568

1. Synthesis of Compound 5

-   -   To a solution of ketone 1 (3.52 g, 19.03 mmol) in MeOH (35 mL)        was added NaBH₄ (775 mg, 20 mmol) in portions at 0° C.    -   The mixture was stirred at 0° C. for 1 h, and then the reaction        was quenched with acetone (5 mL).    -   The reaction mixture was concentrated to half of original volume        via roto-vapor, the residue was diluted with EtOAc (400 mL),        washed with brine (50 mL×3), dried over Na₂SO₄.    -   The solvents were removed under reduced pressure and the residue        was purified via flash column to afford a clear oil (3.5 g,        yield 99%).    -   1H NMR (CDCl₃, 400 MHz) δ: 8.06 (t, J=8.4 Hz, 1H), 7.35 (d,        J=11.6 Hz, 1H), 7.30 (d, J=11.6 Hz, 1H), 5.01-4.99 (m, 1H), 1.52        (d, J=6.4 Hz, 3H).

2. Synthesis of Compound 6

-   -   To a mixture of compound 4 (3.5 g, 18.92 mmol) in THF (100 mL)        was added Br-IPM (6.99 g, 22.70 mmol), PPh₃ (7.44 g, 28.38 mmol)        and then DIAD (5.73 g, 28.38 mmol) at 0° C. under argon.    -   The mixture was stirred at 0° C. for 2 h and then warm to RT        over night while stirring.    -   Solvents were removed under reduced pressure and the residue was        purified via flash column to afford a light yellow oil (4.28 g,        47% yield)

1H NMR (CDCl₃, 400 MHz) δ: 8.09 (t, J=8.0 Hz, 1H), 8.31 (dd, J=2.4, 13.6Hz, 2H), 5.52-5.60 (m, 1H), 3.54-3.19 (m, 8H), 1.63 (d, J=6.4 Hz, 3H).

3. Synthesis of Compound 7

-   -   A mixture of compound 6 (3.95 g, 8.28 mmol), Ag₂O (12 g) in THF        (100 mL) was stirred at 50 C under argon overnight. Solid was        filtered and the filtrate was concentrated to dryness, purified        via flash column to afford a yellow solid (2.28 g, 87% yield).

1H NMR (CDCl₃, 400 MHz) δ: 8.08 (t, J=8.0 Hz, 1H), 7.36 (d, J=11.6 Hz,1H), 7.31 (d, J=8.4 Hz, 1H), 5.70-5.67 (m, 1H), 2.25-2.08 (m, 8H), 1.64(d, J=6.4 Hz, 3H).

4. Synthesis of TH 2803/2804

-   -   To a mixture of imidazole (62 mg, 0.91 mmol) and compound 7 (260        mg, 0.83 mmol) in DMF (5 mL) was added K₂CO₃ (230 mg, 1.66 mmol)        at 0° C. The mixture was stirred at room temperature overnight.    -   Purified via semi-prep HPLC to afford a clear oil.

1H NMR (CDCl₃, 400 MHz) δ: 8.02 (d, J=8.4 Hz, 1H), 7.65-7.2 (m, 2H),7.50 (d, J=1.6 Hz, 1H), 7.24 (s, 1H), 7.08 (s, 1H), 5.81-5.75 (m, 1H),2.22-2.02 (m, 8H), 1.68 (d, J=6.4 Hz, 3H).

This mixture was separated by chiral HPLC to afford TH 2803 and TH 2804.

Other compounds provided herein are made following this method, uponappropriate substitution of starting materials, which are commerciallyavailable or are made according to well-known methods from commerciallyavailable starting material. See, e.g., see U.S. Pat. App. Pub. Nos.2005/0256191, 2007/0032455, and 2009/0136521, and PCT Pub. Nos.2000/064864, 2004/087075, and 2007/002931, each of which is incorporatedherein by reference.

Example 2. In Vitro Human Tumor Cell Line Cytotoxicity Assay

In vitro proliferation data on the H460 non-cell lung cancer human tumorcell line is reported in the table above. IC₅₀ values are reported inmicromolar and result from exposure of compound at variousconcentrations for 2 hrs followed by a wash step and addition of freshmedia followed by growth and cell viability staining and comparison to amedia only treated control.

Specifically, exponentially growing cells are seeded at a density of4×10³ cells per well in a 96 well plate and incubated at 37° C. in 5%CO₂, 95% air and 100% relative humidity for 24 hours prior to additionof test compounds. Compounds are solubilized in 100% DMSO at 200 timesthe desired final test concentration. At the time of drug addition,compounds are further diluted to 4 times the desired final concentrationwith complete medium. Aliquots of 50 μl of compound at specifiedconcentrations are added to microtiter wells already containing 150 μlof medium, resulting in the final drug concentration reported. Afterdrug addition, the plates are incubated for an additional 2 hours at 37°C., 5% CO₂, 95% air, and 100% relative humidity, then the drug is washedoff and fresh medium is added and the plates are incubated for addition70 hrs at 37° C., 5% CO₂, 95% air and 100% relative humidity. At the endof this incubation, the viable cells are quantified using the AlamarBlueassay. The drug concentration resulting in growth inhibition of 50%(IC₅₀) is calculated using Prism software (Irvine, Calif.), and theresults are listed in the table.

The H460 data above demonstrates a substantial anti-tumor effect withenhanced anti-tumor efficacy observed under nitrogen than under air.

On the basis of the favorable in vitro data for these compounds, theiranti-tumor activities in the H460 (NSCLC) human tumor xenograft modelwere evaluated. H460 cells (lx 10⁶) were subcutaneously implanted in theflanks of pathogen-free homozygous female nude mice (nu/nu, CharlesRiver Laboratories). When tumor size reached 100-150 mm³, animals wererandomized to 10 mice per treatment group. All tested compounds wereformulated in 5% DMSO, 5% Tween 80 in D5W. The doses of all thecompounds were chosen on the basis of preliminary studies to define theMTD of each compound when administered daily for 5 days. On the basis ofweight loss and behavioral signs, the MTDs of TH2565 and TH2566 weredetermined to be 2 mg/kg, respectively. The comparative tumor volumereductions for certain compounds are graphically illustrated in FIGS.1A-1C.

It should be understood that although the present invention has beenspecifically disclosed by certain aspects, embodiments, and optionalfeatures, modification, improvement and variation of such aspects,embodiments, and optional features can be resorted to by those skilledin the art, and that such modifications, improvements and variations areconsidered to be within the scope of this disclosure.

The inventions have been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thegeneric disclosure also form part of the invention. In addition, wherefeatures or aspects of the invention are described in terms of Markushgroups, those skilled in the art will recognize that the invention isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group.

1. A compound selected from:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of each thereof, wherein R¹ is: hydrogen, —N₃, CN,halo, NR²¹R²², —OR²³, —SO₂(C₁-C₆ alkyl), C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle,5-15 membered heteroaryl, or ether; each R²¹ and R²² independently ishydrogen, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 memberedheteroaryl, or —SO₂(C₁-C₆ alkyl); or R²¹ and R²² together with thenitrogen atom they are bonded to form a 4-15 membered heterocycle or a5-15 membered heteroaryl; R²³ is hydrogen, C₁-C₆ alkyl, or C₆-C₁₀ aryl;R² and R³ are independently hydrogen or halo; R⁴ is hydrogen, halo,C₁-C₆ alkoxy, C₁-C₆ alkyl, or C₆-C₁₀ aryl, R⁵, R⁷, R⁹, R¹², and R¹⁵independently are hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 memberedheteroaryl; or R⁴ and R⁵ together with the intervening carbon atomsbetween them form a C₅-C₆ cycloalkyl ring; R⁶ and R¹⁰ independently arehydrogen or halo; R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or 5-15 membered heteroaryl; each R¹¹ independently is C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, or C₆-C₁₀ aryl;R¹³, R¹⁴, R¹⁶, and R¹⁷ are independently hydrogen, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkyny, or C₁-C₆ alkoxy; wherein the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy andether groups are optionally substituted.
 2. The compound of claim 1 offormula:


3. The compound of claim 2, wherein R¹ is a non-hydrogen substituent, R²and R³ are hydrogen, and R⁴ is hydrogen or halo, or R⁴ and R⁵ togetherform a 5 membered cycloalkyl group.
 4. The compound of claim 3, whereinR⁴ is hydrogen.
 5. The compound of claim 3, wherein R⁴ is halo.
 6. Thecompound of claim 3, wherein R⁴ is fluoro.
 7. The compound of claim 3,wherein R¹ is NR²¹R²², wherein each R²¹ and R²² independently ishydrogen, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 memberedheteroaryl, or —SO₂(C₁-C₆ alkyl); or R²¹ and R²² together with thenitrogen atom they are bonded to form a 4-15 membered heterocycle or a5-15 membered heteroaryl.
 8. The compound of claim 1 of formula:


9. The compound of claim 1 of formula:


10. The compound of claim 1 of formula:


11. The compound of claim 1 of formula:


12. The compound of claim 1 of formula:


13. The compound of claim 8, wherein R⁸ is hydrogen.
 14. The compound ofclaim 8, wherein R⁸ is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl. 15.The compound of 8, wherein R⁹ is optionally substituted C₁-C₆ alkyl. 16.The compound of claim 9, wherein R⁷ is optionally substituted C₁-C₆alkyl.
 17. The compound of claim 10, wherein R¹² is optionallysubstituted C₁-C₆ alkyl.
 18. The compound of claim 11, wherein R¹⁵ isoptionally substituted C₁-C₆ alkyl.
 19. The compound of claim 3, whereinR⁵ is a non-hydrogen substituent.
 20. The compound of claim 3, whereinR¹ is a non-hydrogen substituent; R² and R³ are hydrogen, and R⁴ ishydrogen or halo, and R⁵ is optionally substituted C₁-C₆ alkyl.
 21. Apharmaceutical composition comprising the compound of claim 1 and atleast one pharmaceutically acceptable excipient.
 22. A method oftreating cancer comprising administering to a patient in need thereof atherapeutically effective amount of the compound of claim 1.